Different types of cancer have been shown to involve at least in part over-activation of receptor-tyrosine-kinases such as cMET, VEGFR, and members of the ErbB-family such as ErbB1 and ErbB2. Cancers include e.g. colorectal cancer, breast cancer, and pancreatic cancer.
The ErbB-family is also designated the subclass I of the receptor tyrosine kinase superfamily. It contains four different receptor proteins: EGFR or ErB1, ErbB2, ErbB3 and ErbB4. In rodents the ErbB2 receptor is referred to as “Neu”. The human forms of the ErbBs are named Her 1-4.
In vertebrates, the “EGF-related ligand family” constitutes the ligands of the ErbB receptors. All these growth factors are produced as transmembrane precursors. Their ectodomains are processed by proteolysis, a step that leads to the shedding of the mature soluble protein. Various studies have identified the ADAM metalloproteinases as being responsible for the cleavage of the ErbB pro-ligands. The ErbB ligands differ in their ability to bind to the ErbB receptors. Based on this binding specificity they can be divided into three groups (reviewed in Olayioye et al., 2000, see references and FIG. 1). The ErbB ligands usually act over short distances as autocrine or paracrine factors. Some ligands like e.g. EGF that is found in all body fluids or Nrg-1 are widely expressed. Also Epiregulin, TGFα and HB-EGF are expressed in many different cell types. ER is expressed in macrophages and in the placenta. TGFα is produced for example in brain cells and keratinocytes, whereas HB-EGF is for example produced by macrophages and keratinocytes. Other ErbB ligands show a more restricted pattern.
The activation of the ErbB receptors, particularly ErbB1 and 2 is deregulated in many human cancers. This deregulation, caused by either overexpression or mutations of the ErbB encoded proteins or by autocrine ligand production, and is characterized by uncontrolled proliferation and migration of cancer cells. The most common type of ErbB1 mutations is the so-called type III mutation. In this case, a deletion of the extracellular domain of the protein leads to constitutive activation of the receptor. ErbB1 proteins carrying a type III mutation are involved in glioma, ovarian, as well as breast cancer (Ekstrand et al, 1992; see references).
Overexpression of ErbB1 on the other hand has been found in squamous-cell carcinomas of head and neck, non-small cell lung cancer, ovarian, lung and breast cancer. While overexpressed, the ErbB1 receptor is still dependent on induction through a ligand in order to signal. The ErbB1 receptor is co-expressed with several of its ligands. TGFα for example is often found to form an autocrine loop that leads to the deregulated activation of ErbB1, for example in lung, colon and breast cancer (Salomon et al, 1995; Umekita et al, 2000).
In contrast to the ErbB1 receptor, no activating mutation has been found for ErbB2 so far. Its activation is mainly due to overexpression, often by means of gene amplification. The increased abundance of ErbB2 molecules in target cells leads to spontaneous dimerization of the ErbB2 proteins and constitutive activation. This kind of receptor activation is found for example in lung, ovarian and stomach cancer, but is especially important in breast cancer where it has been linked to a poor clinical prognosis and resistance to therapy (Ross & Fletcher, 1998, see references).
The ErbB3 receptor has been connected with a resistance against therapies targeting the ErbB2 receptor. Upon blocking of the ErbB2 receptor for example by tyrosine kinase inhibitors (TKIs), the ErbB3 phosphorylation level is increased. This leads to an activation of ErbB3 signaling that promotes cell survival in absence of ErbB2 signaling. In breast cancer, the ErbB3 receptor has been shown to work together with ErbB2, mediating tumor cell division. Their co-expression has been found in many human breast cancers (Sithanandam & Anderson, 2008, see references).
Treatment of breast cancer depends on the underlying molecular mechanisms. Estrogen-receptor dependent breast cancer can be treated e.g. with tamoxifen. ErbB-receptor positive cancers can be treated e.g. with Herceptin®. However, it is known that patients can develop resistance against treatment with e.g. Herceptin®.
Thus, there is a continuing interest and need for pharmaceutically active agents that allow treatment of breast cancers. There is in particular a continuing need for pharmaceutically active agents that allow to selectively address the specific molecular mechanisms underlying types of breast cancer, which on the phenotypic level may not be distinguishable, but are clearly different on the molecular level. There is moreover a need for pharmaceutically active agents that allow treatment of breast cancer patients which have developed resistance against treatment with Herceptin® or small molecule inhibitors of receptor tyrosine kinases (RTK), that inhibit ErbB receptors.